Project Summary HIV-infected individuals have a 2-fold higher risk of myocardial infarction along with higher rates of heart failure and sudden cardiac death. While the mechanism underlying this excess risk remains poorly understood, studies from our groups and others demonstrate that atherosclerosis in the setting of HIV is distinct and characterized by heightened arterial inflammation as assessed by FDG-PET/CT and abnormal endothelial function as assessed by flow-mediated vasodilation of the brachial artery (FMD). These vascular assessments are both improved by lowering of LDL-C using statins or LDL apheresis. Proprotein convertase subtilisin kexin 9 (PCSK9) has emerged as an important pharmacologic target for cholesterol lowering in the general population and in difficult-to-treat populations. Inhibition of PCSK9 with a monoclonal antibody has led to decreases in LDL-cholesterol of ~50-70% and are overall well tolerated without significant side effects. When added on top of statin therapy, PCSK9 inhibition reduced LDL to a median of 30 mg/dL and significantly reduced major cardiovascular events by 15% in a study of > 27,000 individuals with ASCVD. Two agents (Evolocumab, Alirocumab) are FDA-approved. The impact of significant LDL lowering using PCSK9 inhibition on HIV-associated atherosclerosis remains unknown. We propose a single center, double blind, placebo- controlled trial to assess the impact of PCSK9 inhibition on CV risk in the setting of effectively treated HIV- infected individuals with known CVD or at risk for CVD with arterial inflammation at baseline. We propose the following aims: Aim 1: To determine whether PCSK9 inhibition can improve arterial inflammation as assessed by FDG-PET/CT in treated and suppressed HIV-infected individuals. Aim 2: To assess the effect of PCSK9 inhibition on endothelial function as assessed by FMD in treated and suppressed HIV. We will correlate changes in lipid parameters including total cholesterol (TC), HDL-C, triglycerides, non-HDL-C, apolipoprotein B (ApoB), apolipoprotein A-I (ApoA-I), markers of immune activation and inflammation [Lp(a), LpPLA2, sCD14 and T cell activation] assessed with both arterial inflammation (Aim 1) and endothelial function (Aim 2). Aim 3: To perform a pilot evaluation of the impact of PCSK9 inhibition on non-calcified plaque in HIV as measured by serial coronary CT angiography. We will correlate these findings with changes in lipid parameters and markers of inflammation/immune activation assessed in Aim 1; in addition, we will determine whether changes in arterial FDG uptake are associated with changes in coronary plaques. This application combines (1) a successful multidisciplinary team with a strong record of collaboration and expertise in studying interventions in HIV, (2) the ability to rapidly recruit subjects from existing HIV-infected cohorts, (3) leveraging of resources including study drug/placebo provided by industry. Identifying novel therapies to reduce CV risk are essential to improve mortality among HIV-infected individuals, and results from this study will form the groundwork for a future trial to evaluate the impact of PCSK9 inhibition on clinical events in HIV.